Built from Endocrine Lecture 01 (LOs 1–7). Use this to check your work after the active recall sheet.

LO 1

ON EXAM — 5 modes: endocrine (blood), paracrine (local), autocrine (self), JUXTACRINE (contact), nervous (synapse); plus neuroendocrine hybrid. Discriminators: distance, speed, specificity, duration. Exocrine (ducts to surfaces) is NOT a hormonal intercellular mode. IGF-1 autocrine in cancer; gap junctions in myocardium

Five modes of intercellular communication (LO 1)

Mode	Route	Distance / speed	Example(s)
Endocrine	Bloodstream (systemic)	Long-range, slow (min–hr); specificity via target receptor expression	Insulin (β-cell → muscle/liver/fat); cortisol (adrenal → liver/immune)
Paracrine	Diffusion through local ECF — no blood transit	Micrometers, fast; confined by diffusion + local enzymes	Somatostatin (δ-cell) inhibits α/β-cells within islet; histamine in inflammation; prostaglandins
Autocrine	Cell secretes ligand that binds its OWN receptor	Same cell, fast	IGF-1 self-stim on tumor cells (cancer autocrine loop); IL-2 on activated T cells
Juxtacrine	Direct cell-cell contact via membrane-anchored ligands OR gap junctions — NO secretion	Nanometers, variable speed	Notch–Delta/Jagged in development; immunological synapse (MHC–TCR); cardiac gap junctions
Nervous	Neurotransmitter across synaptic cleft	Nanometers, milliseconds, highly targeted by axon wiring	ACh at NMJ; NE at adrenergic synapse; dopamine in CNS

TRAP 1: Autocrine = signals SELF (classic in cancer). Paracrine = signals NEIGHBOR. TRAP 2: Juxtacrine is contact-dependent (Notch-Delta, gap junctions) — often missed.

Neuroendocrine overlap (LO 1)

Hypothalamus → anterior pit

Neuroendocrine: hypothalamic-hypophyseal portal — neurons release hormone into portal capillaries that drain to anterior pit

Sympathetic → adrenal medulla

Neuroendocrine: preganglionic sympathetic releases ACh → chromaffin cells secrete epinephrine into systemic blood (nerve ends at endocrine cell)

Hypothalamus → posterior pit

Neurosecretion: SON/PVN magnocellular neurons synthesize ADH/oxytocin → axons terminate in posterior pit → direct release into blood (neurohemal junction)

Discriminators (LO 1)

Feature	Endocrine	Nervous	Paracrine
Specificity	Target-cell receptor expression	Anatomic wiring to post-synaptic cell	Diffusion distance + local enzymatic degradation
Speed	Seconds–minutes (peptide); min–hr (steroid/thyroid)	Milliseconds	Seconds
Duration	Long (hormone in blood for min–hr)	Brief (rapid reuptake / enzymatic destruction)	Short (local degradation)
Amplification	High (2nd messenger cascades)	Low–moderate (synaptic summation)	Variable (high for eicosanoids/NO)

Endocrine vs EXOCRINE (LO 1)

Exocrine delivery

Product delivered through a DUCT onto an external/luminal surface. NOT a hormonal intercellular mode — it's a secretion pathway

Exocrine examples

Salivary amylase, pancreatic lipase, sweat, sebum, tears, gastric HCl

Pancreas dual

Endocrine (islet cells → insulin/glucagon/somatostatin into blood) + Exocrine (acini → digestive enzymes via ducts to duodenum)

Special modes (LO 1)

Nerve-made hormone in blood

Neuroendocrine — neuron releases hormone into blood (ADH, oxytocin, hypothalamic releasing hormones, adrenal medullary epinephrine)

Connexons

Juxtacrine via gap junctions — ions + small molecules (<1 kDa) pass directly between cells. Cardiac electrical coupling is classic

Pheromones

Signal across individuals of same species. Well-described in insects/rodents; contested in humans

Prostaglandins / histamine

Primarily paracrine/autocrine — made on demand from arachidonic acid, act locally, degraded in seconds–minutes

LO 2

ON EXAM — classify by 3 properties: STRUCTURE (peptide/steroid/amine), SOLUBILITY (water vs lipid → predicts receptor location), STORABILITY (vesicles vs on-demand vs uniquely on thyroglobulin). Thyroid = amine structurally but lipid-soluble + nuclear receptor (EXCEPTION).

Hormone classes (LO 2)

Property	Peptide / protein	Steroid	Catecholamine	Thyroid (exception)
Structure	AA polymers — from short (TRH) to glycoproteins (FSH/LH/TSH/hCG)	Four-ring cholesterol-derived (cyclopentanoperhydrophenanthrene)	Catechol (dihydroxybenzene) + ethylamine; from tyrosine	Iodinated tyrosine residues coupled (T₃: 3 I; T₄: 4 I)
Solubility	Water-soluble; cannot cross membrane	Lipid-soluble; crosses plasma + nuclear membranes	Water-soluble	LIPID-soluble (iodination → hydrophobic)
Storability	Stored in large secretory vesicles; released on demand	NOT stored — made on demand; release rate = synthesis rate	Stored in vesicles (VMAT2 loaded)	UNIQUELY stored extracellularly on thyroglobulin in colloid (~2–3 mo reserve)
Receptor	Cell surface (GPCR, RTK, JAK-STAT)	Intracellular / nuclear	Cell surface (α/β adrenergic GPCRs)	NUCLEAR (TR + RXR)
Action speed	Seconds–minutes	Hours–days	Seconds	Hours–days
Examples	Insulin, glucagon, GH, PTH, ADH, oxytocin, ACTH, TSH, LH, FSH, hCG	Cortisol, aldosterone, estradiol, progesterone, testosterone, vit D	Epinephrine, norepinephrine, dopamine	T₃ (active), T₄ (prohormone)

Why thyroid is the exception (LO 2)

Classified as amine because…

Synthesized from coupled iodinated TYROSINE residues within the thyroglobulin scaffold — biochemically an amine

Lipid-soluble because…

Iodination of tyrosine dramatically increases hydrophobicity — structurally amine but functionally steroid-like

Receptor

Nuclear TR; Type 2 NR that heterodimerizes with RXR on TREs (DR-4 direct repeats)

Unique storage

Extracellular storage on thyroglobulin in colloid; stored as iodinated MIT/DIT which couple to form T₃/T₄; 2–3 month reserve of preformed hormone

Storability drives release kinetics (LO 2)

Class	Stimulus → release	Time to blood peak
Peptide	Stimulus → Ca²⁺ influx → vesicle exocytosis of preformed hormone	Seconds–minutes
Steroid	Stimulus (ACTH/LH) → StAR induction → CYP cascade → new synthesis	15–30 min for cortisol; hours for full response
Catecholamine	Sympathetic firing / ACTH (portal) → Ca²⁺ → vesicle exocytosis	Seconds
Thyroid	TSH → endocytosis of thyroglobulin-bound colloid → lysosomal proteolysis releases T₃/T₄	Hours (iodination + proteolysis steps)

LO 3

ON EXAM — Tyr → DOPA (TH, RATE-LIMITING, needs BH₄, cytosol); DOPA → DA (AADC, PLP); DA loaded into vesicle by VMAT2; DA → NE (DBH, inside vesicle, Cu²⁺ + ascorbate); NE exits vesicle, methylated in cytosol by PNMT (cortisol-induced, adrenal medulla only); degraded by COMT + MAO → metanephrines, VMA, HVA

Full catecholamine pathway (LO 3)

Substrate	Enzyme	Cofactor(s)	Location	Product	Clinical hook
Phenylalanine	Phenylalanine hydroxylase (PAH)	BH₄ + O₂	Hepatocyte cytosol (liver)	Tyrosine	PAH deficiency = PKU; BH₄ deficiency = atypical PKU (also low DA, 5-HT)
Tyrosine	Tyrosine hydroxylase (TH) — RATE-LIMITING	BH₄ + O₂ + Fe²⁺	Cytosol of catecholamine cells (sympathetic neurons, adrenal medulla, dopaminergic neurons)	L-DOPA	TH deficiency → dopa-responsive dystonia (Segawa). Metyrosine (AMPT) inhibits TH pre-op for pheochromocytoma
L-DOPA	Aromatic L-amino acid decarboxylase (AADC / DOPA decarboxylase)	PLP (vitamin B₆)	Cytosol	Dopamine	Carbidopa = peripheral AADC inhibitor (doesn't cross BBB); given with L-DOPA for Parkinson
Dopamine	Dopamine β-hydroxylase (DBH)	Cu²⁺ + ascorbate + O₂	INSIDE synaptic vesicles (DA loaded by VMAT2)	Norepinephrine	DBH deficiency: orthostatic hypotension, ptosis, anhidrosis; high DA, low NE/Epi. Tx: droxidopa
Norepinephrine	Phenylethanolamine N-methyltransferase (PNMT)	SAM (S-adenosyl methionine)	CYTOSOL of adrenal medulla chromaffin cells (absent in sympathetic ganglia)	Epinephrine	PNMT induced by high local cortisol via cortico-medullary portal system. Adrenalectomy/hypopituitarism → PNMT ↓

Rate-limiting step: tyrosine hydroxylase (LO 3)

Rate-limiting step

Tyrosine hydroxylase (TH) — Tyr → L-DOPA. Controls total catecholamine output

Essential cofactor

BH₄ (tetrahydrobiopterin); also Fe²⁺ and O₂

Acute activation

Phosphorylation by PKA, PKC, CaMK at serines (Ser-19, Ser-31, Ser-40) → rapid activation

Chronic upregulation

Transcriptional induction by sympathetic activity (cold, stress) in neurons; by glucocorticoids in adrenal medulla. Hours–days timescale

Feedback inhibitor

End products (dopamine, NE) bind TH regulatory site → competitive inhibition with BH₄

TH inhibitor drug

Metyrosine (α-methyl-para-tyrosine, AMPT) — competitive TH inhibitor; used pre-op for pheochromocytoma to deplete catecholamine stores

Vesicle biology — VMAT2 step (LO 3)

Vesicular enzyme

Dopamine β-hydroxylase (DBH) — only intravesicular synthesis enzyme

DA loading

Vesicular Monoamine Transporter 2 (VMAT2) — H⁺/monoamine antiporter (driven by V-ATPase H⁺ gradient)

VMAT2 drugs

Tetrabenazine, valbenazine, deutetrabenazine — used for Huntington chorea and tardive dyskinesia (deplete presynaptic DA stores)

PNMT location

CYTOSOL — NE must leave vesicle to be methylated, then Epi re-enters (since PNMT is cytosolic and SAM is cytosolic)

NE shuttle

DA in vesicle (VMAT2) → DBH makes NE → NE exits → PNMT methylates in cytosol → Epi re-enters via VMAT2. Required because SAM + PNMT are cytosolic

PNMT uniqueness to adrenal medulla (LO 3)

Anatomic arrangement

Cortico-medullary portal venous system — cortical cortisol drains through the medulla, bathing chromaffin cells in cortisol ~100× systemic levels

Cortisol on PNMT

Cortisol is a potent inducer of PNMT gene transcription → uniquely present in adrenal medulla

Sympathetic ganglia

Post-ganglionic sympathetic neurons have no cortisol exposure → no PNMT → NE is the end product, not Epi

PNMT loss

Adrenalectomy, hypopituitarism, or chronic exogenous steroids (suppress pituitary ACTH) → cortex loses cortisol output → medullary PNMT falls → Epi/NE ratio decreases

Degradation & urinary metabolites (LO 3)

Substrate	Enzymes	Urinary metabolite	Clinical use
Dopamine	COMT (cytosolic) + MAO (mitochondrial)	HVA (homovanillic acid)	Neuroblastoma screening; dopamine-secreting tumors
Norepinephrine	COMT + MAO. Intermediate: normetanephrine	VMA (vanillylmandelic acid)	Pheochromocytoma — plasma free metanephrines (best sensitivity); 24-h urinary metanephrines + VMA
Epinephrine	COMT + MAO. Intermediate: metanephrine	VMA	Pheochromocytoma. Medullary-origin tumors make both NE + Epi; extra-adrenal paraganglioma usually NE only

HIGH-YIELD: Plasma free metanephrines are the best screening test for pheochromocytoma. VMA (final NE/Epi product) and HVA (dopamine product) are classically used for neuroblastoma screening in children.

Enzyme / cofactor deficiencies (LO 3)

PAH deficiency

PKU (classic: PAH mutation; atypical: BH₄ synthesis defect). Tx: Phe-restricted diet; atypical needs BH₄ + L-DOPA + 5-HTP (BH₄ is also cofactor for TH + TPH)

TH deficiency

Dopa-responsive dystonia (Segawa) — childhood dystonia with dramatic response to low-dose L-DOPA; diurnal (worse evening)

AADC deficiency

Severe infantile movement disorder; low DA AND 5-HT (AADC also decarboxylates 5-HTP). Oculogyric crises, autonomic dysfunction. Poor response to L-DOPA. Gene therapy now approved

DBH deficiency

Orthostatic hypotension + ptosis + anhidrosis + sexual dysfunction; high plasma DA, absent NE/Epi. Tx: droxidopa (L-threo-DOPS) — AADC converts it to NE, bypassing DBH

L-DOPA alone

Peripheral AADC converts most to DA → nausea, vomiting, orthostatic hypotension; tiny fraction reaches brain. Carbidopa (peripheral AADC inhibitor — doesn't cross BBB) lets more L-DOPA reach brain

Entacapone

COMT inhibitor — blocks peripheral methylation of L-DOPA → prolongs half-life. Added to carbidopa/L-DOPA for "wearing-off" in advanced Parkinson disease

LO 4

ON EXAM — INITIAL STEP is the rate-limiting one. TWO sub-steps: (1) StAR shuttles cholesterol OMM → IMM (acute regulated step, ACTH-induced via cAMP/PKA); (2) CYP11A1 (P450scc/desmolase) on IMM cleaves cholesterol → PREGNENOLONE. Cofactors: O₂ + NADPH via adrenodoxin/adrenodoxin reductase. StAR mutation → congenital lipoid adrenal hyperplasia. CYP11A1 deficiency → failure of ALL steroidogenesis

Cholesterol sources (LO 4)

Source	Mechanism / transporter	Relative contribution
Circulating LDL	LDL receptor (LDLR) → clathrin-mediated endocytosis → lysosomes → free cholesterol	MAIN source in humans (~80% of basal adrenal cholesterol)
Circulating HDL	SR-BI (scavenger receptor class B, type 1) — selective cholesteryl ester uptake without particle endocytosis	Minor in humans; major in rodents. More important in chronic ACTH stimulation
De novo synthesis	HMG-CoA reductase pathway in smooth ER (acetyl-CoA → mevalonate → cholesterol)	Minority under basal conditions; can compensate when LDL limited
Lipid droplets	Cholesteryl Ester Hydrolase (CEH/HSL) — activated by PKA under ACTH stim → mobilizes stored cholesterol	Rapid-access reserve for acute steroidogenesis (minutes after ACTH spike)

KEY: Adrenal cortex relies mainly on LDL-derived cholesterol via LDLR. Stored cholesteryl esters in lipid droplets are mobilized by CEH/HSL, activated by PKA in the ACTH signaling cascade.

Two sub-steps of the initial step (LO 4)

Sub-step	Enzyme/protein	Reaction	Site	Regulation
1. Shuttle	StAR (Steroidogenic Acute Regulatory protein)	Transports cholesterol OMM → IMM (no enzymatic modification)	Mitochondrial membranes	ACUTE rate-limiting (REGULATED) step; induced by ACTH via cAMP/PKA in minutes
2. Cleavage	CYP11A1 (P450scc / desmolase)	Cholesterol → pregnenolone + isocaproaldehyde (cleaves C20–C22, hydroxylates C20+C22)	Inner mitochondrial membrane (IMM)	Chronically induced by ACTH (transcription); cofactor supply modulates rate

StAR (LO 4)

Full name

Steroidogenic Acute Regulatory protein

What StAR moves

CHOLESTEROL (not pregnenolone)

From → to

OUTER mitochondrial membrane (OMM) → INNER mitochondrial membrane (IMM), across intermembrane space

Induction speed

Minutes (ACUTE regulated step) — responsible for rapid cortisol rise after ACTH stimulation

ACTH cascade

ACTH → MC2R on adrenocortical cell → Gs → cAMP → PKA → (1) phosphorylates CREB → StAR transcription; (2) phosphorylates HSL/CEH → mobilizes stored cholesterol; (3) directly phosphorylates StAR to enhance activity

StAR mutation

Congenital Lipoid Adrenal Hyperplasia (lipoid CAH) — severe salt-wasting adrenal insufficiency; 46,XY with female external genitalia (no testosterone); massive adrenal cholesterol accumulation; autosomal recessive

CYP11A1 / P450scc / desmolase (LO 4)

Substrate → product

Cholesterol → pregnenolone + isocaproaldehyde

Cofactors

NADPH + O₂

Electron donors

Adrenodoxin reductase (FAD) → adrenodoxin (iron-sulfur protein) → CYP11A1 — the mitochondrial P450 electron shuttle

Biochemical rate-limiting

CYP11A1 catalyzes the first COMMITTED reaction of steroidogenesis. Without it, no steroid of ANY class can form. StAR governs FLUX; CYP11A1 performs CATALYSIS — both are required

CYP11A1 loss

CYP11A1 deficiency → phenotype similar to StAR: salt-wasting adrenal insufficiency, 46,XY under-virilization (female external), no sex hormone at puberty. Extremely rare

Why pregnenolone matters (LO 4)

Pregnenolone is precursor to

Cortisol (glucocorticoid), aldosterone (mineralocorticoid), testosterone/DHEA (androgens), estradiol (via aromatase), progesterone (progestagens). Vitamin D shares cholesterol but splits off earlier

Acute ACTH response

StAR induction + cholesterol ester hydrolysis → rapid cholesterol flux → CYP11A1 → pregnenolone. Cortisol rises within 15–30 min

Chronic ACTH response

Transcriptional upregulation of ALL steroidogenic enzymes (StAR, CYP11A1, CYP17, CYP21, CYP11B1) → steroidogenic capacity increases. Days–weeks → bilateral adrenal hyperplasia

LH analog

LH binds LHCGR (Gs GPCR) on theca/Leydig/corpus luteum → cAMP/PKA → same StAR + CYP11A1 mechanism as ACTH in adrenal

Clinical correlates (LO 4)

Lipoid CAH

StAR loss → cholesterol ester accumulation in cortex (massive bilateral adrenal enlargement); complete adrenal failure with salt-wasting crisis in infancy; 46,XY have female external phenotype (no fetal testicular testosterone)

Ketoconazole

Blocks CYP11A1 (+ CYP17, CYP21, aromatase) → steroidogenesis inhibitor. Off-label in Cushing syndrome to lower cortisol. Side effects: hypogonadism, gynecomastia, adrenal insufficiency

Ketoconazole side effects

Because it blocks many CYPs: hypogonadism (low testosterone from testicular CYPs), gynecomastia (shift to estrogen), adrenal insufficiency (low cortisol)

Hyperlipidemia bottleneck

StAR is the rate-limiting SHUTTLE — cholesterol supply is NOT the bottleneck. Rate is controlled by ACTH/PKA/StAR, not by cholesterol concentration. Hence hyperlipidemia does not cause hypercortisolism

LO 5, 6, 7

ON EXAM — Carrier proteins extend half-life; only FREE hormone is active (free-hormone hypothesis). Pregnancy/OCPs → TBG ↑ → total T₄ ↑, free normal. Receptors: surface (GPCR, RTK, JAK-STAT, LGIC, GC) for water-soluble; nuclear (Type 1 steroid HSP/cyto/homodimer vs Type 2 TR/VDR/RAR with RXR) for lipid-soluble. Sensitivity: receptor number (up/down), affinity (K_d), spare receptors, desensitization, post-receptor signaling

Carrier proteins (LO 5)

Carrier	Binds	Effect on half-life	Clinical pearl
SHBG	Sex steroids — testosterone > estradiol	Extends half-life; acts as reservoir	Pregnancy/hyperthyroid → ↑. Obesity/hypothyroid/androgens → ↓ (↑ free T bioactivity)
CBG (transcortin)	Cortisol	Extends half-life	Pregnancy/OCPs → CBG ↑ (total cortisol ↑, free normal). Liver failure/nephrotic → CBG ↓
TBG	T₄ (>70%), some T₃	Extends half-life	Pregnancy/OCPs → TBG ↑ → total T₄ ↑, free T₄ normal, TSH normal — EUTHYROID
Albumin	Low-affinity, high-capacity carrier for many hormones	Modest half-life extension	Drops in liver/nephrotic disease → affects total but not free

Active fraction

FREE (unbound) hormone — only it enters cells + binds receptors

Pregnancy T₄

Total T₄ ↑ (estrogen → TBG ↑); free T₄ normal; TSH low-normal 1st trimester (hCG cross-stim) then normalizes. Patient EUTHYROID

Order which

FREE T₄ (or free testosterone/free cortisol) when binding-protein status is changing — pregnancy, OCPs, liver disease, nephrotic

Receptor classification (LO 6)

Feature	Cell-surface	Nuclear
Ligand solubility	Water-soluble (peptides, catecholamines)	Lipid-soluble (steroids, thyroid, vit D, retinoic acid)
Signal mechanism	Second messengers (cAMP, IP₃/Ca²⁺, DAG, cGMP) + phosphorylation cascades	Direct gene transcription via HRE binding
Action speed	Seconds–minutes	Hours–days
Ligand classes	Peptides, catecholamines, neuropeptides	Steroids, thyroid, vit D, retinoic acid, PPAR/LXR/FXR ligands
Exception	THYROID (amine) uses NUCLEAR receptor; VITAMIN D also nuclear — both break the "amine = surface" rule

Membrane receptor families (LO 6)

GPCR

Gs → ↑cAMP (glucagon, β-adrenergic, ACTH, TSH, LH, FSH, ADH-V2). Gi → ↓cAMP (α₂, M₂, D₂, somatostatin, opioid). Gq → IP₃/DAG/Ca²⁺ (TRH, GnRH, α₁, V₁, oxytocin)

RTK

Ligand → dimerization → auto-phosphorylation → MAPK + PI3K-AKT. Insulin, IGF-1, EGF, FGF, PDGF, VEGF

JAK-STAT

Dimer → JAK phosphorylates STAT → STAT dimer to nucleus. GH, prolactin, EPO, leptin, cytokines

Guanylyl cyclase

ANP (membrane GC → ↑cGMP → vasodilation); NO (soluble GC); ST enterotoxin

Ligand-gated

Nicotinic ACh (NMJ); GABA-A (Cl^–); glycine; 5HT₃

Nuclear receptor Type 1 vs Type 2 (LO 6)

Feature	Type 1 (steroid)	Type 2 (TR/VDR/RAR/PPAR)
Resting location	Cytoplasm, bound to HSP90	Nucleus, on DNA bound to corepressor
Dimer	Homodimer (GR-GR, ER-ER, AR-AR)	Heterodimer with RXR
HSP90 at rest	YES — displaced by ligand	NO — ligand swaps corepressor for coactivator
Members	GR, MR, ER, PR, AR	TR, VDR, RAR, PPAR, LXR, FXR

Cellular sensitivity (LO 7)

Receptor number

Upregulation: chronic low ligand (β-receptor ↑ with prolonged β-blocker → rebound risk). Downregulation: chronic high ligand (insulin receptor internalized with hyperinsulinemia → insulin resistance)

K_d

LOW K_d = HIGH affinity (less ligand needed for half-occupancy). HIGH K_d = LOW affinity

Spare receptors

Receptor reserve — full response at <100% occupancy — EC₅₀ < K_d. Classic: insulin on adipocytes; β-adrenergic in heart

Desensitization

(1) Receptor phosphorylation (GRKs) → β-arrestin → uncoupling. (2) Receptor internalization (endocytosis). (3) Transcriptional downregulation. (4) Feedback proteins (SOCS, etc.)

Tachyphylaxis

Rapid loss of response with repeated dosing over min–hr (independent of downregulation). Example: oxymetazoline nasal decongestant — rapid β₂ desensitization

Post-receptor signaling

Altered 2nd messenger generation, kinase/phosphatase balance, transcription factor availability, effector abundance — same occupancy, different response in different cell states

LO 1–7 · USMLE Step 1 Style

9 questions — answers pre-revealed. Weighted toward expanded LOs (signaling, catecholamines, steroid initial step).

Q1. A pancreatic islet δ-cell releases somatostatin, which binds receptors on nearby α- and β-cells within the same islet, inhibiting their secretion. Somatostatin is NOT appreciable in systemic circulation. Which mode?

A. Endocrine
B. Paracrine
C. Autocrine
D. Juxtacrine
E. Neuroendocrine

B — Paracrine.
Local diffusion to adjacent cells of the same tissue without entering systemic blood. Contrast: endocrine (blood/systemic), autocrine (same cell), juxtacrine (membrane-membrane contact), neuroendocrine (neuron releases into blood).

Q2. A newly identified signaling molecule binds a transmembrane ligand on an adjacent cell without any secretion. Binding triggers signaling in BOTH cells simultaneously. Which mode?

A. Endocrine
B. Paracrine
C. Autocrine
D. Juxtacrine (contact-dependent)
E. Exocrine

D — Juxtacrine.
Contact-dependent signaling via membrane-anchored ligands (Notch-Delta) or gap junctions (connexons). Examples: Notch-Delta in development; immunological synapse; cardiac myocyte gap junctions (electrical coupling). No secreted intermediate.

Q3. A 19-year-old with Parkinson-like early-childhood dystonia has low CSF dopamine, undetectable HVA, and NORMAL phenylalanine. L-DOPA + carbidopa dramatically improves symptoms. Which enzyme is deficient?

A. Phenylalanine hydroxylase
B. Tyrosine hydroxylase
C. AADC
D. DBH
E. PNMT

B — Tyrosine hydroxylase (TH) deficiency.
TH is the rate-limiting enzyme (Tyr → L-DOPA). Deficiency → low DA, low NE, low Epi, low HVA. Phe normal (PAH intact). L-DOPA BYPASSES TH; carbidopa prevents peripheral AADC conversion so more L-DOPA reaches brain. AADC deficiency would NOT respond to L-DOPA.

Q4. A 28-year-old man: chronic orthostatic hypotension, ptosis, anhidrosis. Plasma NE very low; dopamine HIGH; DOPA normal. Improves on droxidopa. Which enzyme is deficient?

A. TH
B. AADC
C. DBH
D. PNMT
E. COMT

C — Dopamine β-hydroxylase (DBH) deficiency.
DBH converts DA → NE INSIDE the vesicle; loss → HIGH dopamine (spills over), LOW NE/Epi. Classic: severe orthostatic hypotension, ptosis, anhidrosis, sexual dysfunction. Tx: droxidopa (L-threo-DOPS) — AADC converts it to NE, bypassing DBH.

Q5. Long-term high-dose prednisone decreases PNMT expression in the adrenal medulla. Which BEST explains the normal relationship between cortisol and PNMT?

A. PNMT is a Gs-coupled receptor internalized by cortisol
B. PNMT is INDUCED by very high local cortisol reaching the medulla via the adrenal cortico-medullary portal system; exogenous steroids suppress pituitary ACTH → cortical cortisol falls → PNMT ↓
C. PNMT is a cortisol-binding protein
D. PNMT uses cortisol as a cofactor
E. PNMT and cortisol are unrelated

B — Cortical cortisol INDUCES medullary PNMT via local portal.
Adrenal has cortico-medullary portal venous system → chromaffin cells see cortisol ~100× systemic levels → cortisol induces PNMT transcription → NE → Epi. Exogenous steroids suppress ACTH → cortical cortisol falls → PNMT ↓. Explains why sympathetic ganglia (no cortisol exposure) make NE but not Epi.

Q6. A neonate: ambiguous genitalia, salt-wasting, bilaterally enlarged adrenals on imaging. ALL steroid hormones are UNDETECTABLE. Cholesteryl esters accumulate in adrenal cortex. Which enzyme/protein is defective?

A. 21-hydroxylase
B. 11β-hydroxylase
C. 17α-hydroxylase
D. Steroidogenic Acute Regulatory protein (StAR)
E. Aldosterone synthase

D — StAR mutation (congenital lipoid adrenal hyperplasia).
If cholesterol can't be shuttled OMM → IMM, CYP11A1 has no substrate → NO pregnenolone → NO steroids of any class. Cholesterol accumulates in lipid droplets (massive adrenal enlargement). Salt-wasting crisis; 46,XY under-virilize (no testicular testosterone). Confirms StAR as regulated rate-limiting step.

Q7. In vitro, adrenal mitochondria given excess cholesterol + adrenodoxin + adrenodoxin reductase + NADPH + O₂. Which enzyme DIRECTLY converts cholesterol to pregnenolone, and where?

A. CYP21A2 — smooth ER
B. CYP17A1 — smooth ER
C. CYP11A1 (P450scc / desmolase) — inner mitochondrial membrane
D. 3β-HSD — smooth ER
E. HMG-CoA reductase — ER

C — CYP11A1 on the INNER mitochondrial membrane.
CYP11A1 (= P450scc = “cholesterol side-chain cleavage enzyme” = “desmolase”) sits on the IMM and cleaves the cholesterol side chain to yield pregnenolone. Cofactors: NADPH, O₂, and adrenodoxin/adrenodoxin reductase electron shuttle. Substrate access depends on StAR delivery.

Q8. A 35-year-old woman on OCPs has elevated total T₄ but normal TSH and free T₄, and is clinically euthyroid. Best explanation?

A. Thyroid adenoma
B. Estrogen-driven increase in TBG raises total T₄; free T₄ normal
C. Thyroid-stimulating antibody
D. Subclinical hyperthyroidism
E. Hypoalbuminemia

B — Estrogen raises TBG → total T₄ ↑ but free unchanged.
Free-hormone hypothesis: only free hormone is active. Estrogen (pregnancy, OCPs) increases hepatic TBG → more bound T₄ → total ↑, but pituitary sees normal free T₄ → TSH normal → euthyroid. Order free T₄ whenever binding-protein status is changing.

Q9. Tissue A reaches maximum response at 10% receptor occupancy; tissue B only at >95%. Which BEST describes tissue A?

A. Higher K_d than B
B. Spare receptors → EC₅₀ < K_d
C. No receptors
D. Tachyphylaxis
E. Competitive antagonist

B — Spare receptors (EC₅₀ < K_d).
Spare receptors = full biological response at partial receptor occupancy → EC₅₀ (half-max EFFECT) < K_d (half-max BINDING). Downstream signaling amplification drives full response at low occupancy. Classic: insulin on adipocytes; β-adrenergic in heart. Tissues without spare receptors show EC₅₀ = K_d.

Intro to Hormones — Answer Key